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| ID | Type | Description | Link |
|---|---|---|---|
| 2015-001371-41 | EudraCT Number | EudraCT |
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To assess the influence of multiple doses of BI 425809 on single dose pharmacokinetics of midazolam (CYP3A4 probe drug), warfarin (CYP2C9 probe drug), omeprazole (CYP2C19 probe drug) and digoxin (P-gp probe drug)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Probe drugs (Reference (R))/BI 425809+Probe drugs (Test (T)) | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midazolam | Drug |
| ||
| Warfarin |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Short-term BI 425809 (after 3rd dose) plus midazolam": Within 3 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of midazolam on Day 3 of Treatment Period 2. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Within 3 h before and up to 24h after administration of midazolam/probe drug cocktail. For detailed timeframe please see outcome measure description. |
| Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of omeprazole in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
| Area Under the Concentration-time Curve of S-warfarin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of S-warfarin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. |
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Inclusion criteria:
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| 1346.22.1 Boehringer Ingelheim Investigational Site | Biberach | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36700734 | Derived | Desch M, Schlecker C, Hohl K, Liesenfeld KH, Chan T, Muller F, Wunderlich G, Keller S, Ishiguro N, Wind S. Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, With Cytochrome P450 and P-Glycoprotein Substrates: Findings From In Vitro Analyses and an Open-Label, Single-Sequence Phase I Study. J Clin Psychopharmacol. 2023 Mar-Apr 01;43(2):113-121. doi: 10.1097/JCP.0000000000001656. Epub 2023 Jan 26. |
| Label | URL |
|---|---|
| Related Info | View source |
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Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases(in case of low number of patients and therefore limitations with anonymization).
For more details refer to:
https://www.clinicalstudies.boehringer-ingelheim.com/msw/datasharing
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All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
This trial in healthy male subjects applied an open-label, crossover design consisting of 2 treatment periods with a fixed sequence. It assessed the influence of multiple doses of BI 425809 (14 days) on single dose pharmacokinetics (PK) of midazolam, warfarin, omeprazole, and digoxin. Furthermore, the short-term effect of BI 425809 on single dose midazolam PK was investigated.
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| ID | Title | Description |
|---|---|---|
| FG000 | Probe Drugs (Reference (R))/BI 425809+Probe Drugs (Test (T)) | Treatment Period 1 (administration of reference treatment (R)): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water. Treatment Period 2 (administration of test treatment (T)): From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 3 of Treatment Period 2 participants administered a single dose of 2 mg of midazolam. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water. Between Treatment Period 1 and Treatment Period 2 were at least 5 days wash-out. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1: Treatment period 1 (06 days) |
|
| ||||||||||||||||||
| Washout Period (05 days) |
| |||||||||||||||||||
| Period 2: Treatment period 2 (15 days) |
|
The Treated Set (TS) included all subjects allocated to a study subject number and who started Visit 2, who were documented to have taken at least one dose of trial medication. The TS was used for all safety analyses and analyses of demographic data.
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| ID | Title | Description |
|---|---|---|
| BG000 | Probe Drugs (Reference (R))/BI 425809+Probe Drugs (Test (T)) | Treatment Period 1 (administration of reference treatment (R)): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water. Treatment Period 2 (administration of test treatment (T)): From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 3 of Treatment Period 2 participants administered a single dose of 2 mg of midazolam. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water. Between Treatment Period 1 and Treatment Period 2 were at least 5 days wash-out. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Short-term BI 425809 (after 3rd dose) plus midazolam": Within 3 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of midazolam on Day 3 of Treatment Period 2. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary Pharmacokinetic (PK) endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram (ng)*hour (h)/millilitre (mL) | Within 3 h before and up to 24h after administration of midazolam/probe drug cocktail. For detailed timeframe please see outcome measure description. |
From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment Period 1: Probe Drugs | Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim Call Center | Boehringer Ingelheim | 1800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| D014859 | Warfarin |
| D009853 | Omeprazole |
| D004077 | Digoxin |
| C000634404 | BI 425809 |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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Participants administered first probe drugs during the reference period and BI 425809 + Probe drugs during the test period.
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| Drug |
|
| Omeprazole | Drug |
|
| Digoxin | Drug |
|
| BI 425809 | Drug | Tablet |
|
|
| Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
| Area Under the Concentration-time Curve of Digoxin From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of digoxin from 0 to the time of the last quantifiable data point (AUC0-tz) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 10 minutes before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 2 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 4 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 11 of Treatment Period 2. | Blood sampling was done before and up to 95 after administration of digoxin. For detailed timeframe please see outcome measure description. |
| Maximum Concentration of Midazolam in Plasma (Cmax) | Maximum measured concentration of midazolam in plasma (Cmax) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Short-term BI 425809 (after 3rd dose) plus midazolam": Within 3 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of midazolam on Day 3 of Treatment Period 2. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Within 3 h before and up to 24h after administration of midazolam/probe drug cocktail. For detailed timeframe please see outcome measure description. |
| Maximum Concentration of Omeprazole in Plasma (Cmax) | Maximum measured concentration of omeprazole in plasma (Cmax) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
| Maximum Concentration of S-warfarin in Plasma (Cmax) | Maximum measured concentration of S-warfarin in plasma (Cmax) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
| Maximum Concentration of Digoxin in Plasma (Cmax) | Maximum measured concentration of digoxin in plasma (Cmax) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 10 minutes before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 2 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 4 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 11 of Treatment Period 2. | Blood sampling was done before and up to 95 after administration of digoxin. For detailed timeframe please see outcome measure description. |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
|
|
|
| Primary | Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of omeprazole in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
|
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|
|
| Primary | Area Under the Concentration-time Curve of S-warfarin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of S-warfarin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
|
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|
|
| Primary | Area Under the Concentration-time Curve of Digoxin From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz) | Area under the concentration-time curve of digoxin from 0 to the time of the last quantifiable data point (AUC0-tz) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 10 minutes before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 2 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 4 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 11 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Blood sampling was done before and up to 95 after administration of digoxin. For detailed timeframe please see outcome measure description. |
|
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|
|
| Primary | Maximum Concentration of Midazolam in Plasma (Cmax) | Maximum measured concentration of midazolam in plasma (Cmax) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Short-term BI 425809 (after 3rd dose) plus midazolam": Within 3 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of midazolam on Day 3 of Treatment Period 2. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Within 3 h before and up to 24h after administration of midazolam/probe drug cocktail. For detailed timeframe please see outcome measure description. |
|
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|
|
| Primary | Maximum Concentration of Omeprazole in Plasma (Cmax) | Maximum measured concentration of omeprazole in plasma (Cmax) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
|
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|
|
| Primary | Maximum Concentration of S-warfarin in Plasma (Cmax) | Maximum measured concentration of S-warfarin in plasma (Cmax) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description. |
|
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|
|
| Primary | Maximum Concentration of Digoxin in Plasma (Cmax) | Maximum measured concentration of digoxin in plasma (Cmax) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 10 minutes before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 2 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 4 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 11 of Treatment Period 2. | Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Blood sampling was done before and up to 95 after administration of digoxin. For detailed timeframe please see outcome measure description. |
|
|
|
|
| 0 |
| 13 |
| 4 |
| 13 |
| EG001 | Treatment Period 2: BI 425809 Plus Probe Drugs | From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water. | 0 | 12 | 11 | 12 |
| EG002 | Overall Treatment | Single doses of probe drugs Midazolam-ratiopharm® 2 mg/mL solution, 1 mL (corresponds to 2 mg midazolam), Coumadin® 5 mg tablet, 2 tablets (corresponds to 10 mg warfarin) warfarin, Omeprazol STADA® 20 mg capsule (1 capsule (corresponds to 20 mg omeprazole)), Lanicor® 0.25 mg digoxin tablet (1 tablet (corresponds to 0.25 mg digoxin)) administered orally with 240 mL of water. Multiple doses of 25 mg BI 425809 plus single doses of probe drugs midazolam (twice), warfarin, omeprazole, digoxin administered orally with 240 mL of water. | 0 | 13 | 13 | 13 |
| Rhinitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Conjunctivitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Dry eye | Eye disorders | MedDRA 18.1 | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | MedDRA 18.1 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 18.1 | Systematic Assessment |
|
| Arthropod bite | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
|
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| D006571 | Heterocyclic Compounds |
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
| D001562 | Benzimidazoles |
| D004071 | Digitalis Glycosides |
| D002298 | Cardenolides |
| D002301 | Cardiac Glycosides |
| D002297 | Cardanolides |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| Other |
| Other |
| The statistical analysis assesses the effect of multiple doses BI 425809 on the Cmax of midazolam. Adjusted gMean ratio and 95% confidence interval were calculated using the Analysis of Variance (ANOVA) model which included the effects accounting for 'subject' and 'treatment' as sources of variation. The effect 'subject' was considered as random, whereas the effect 'treatment' was considered as fixed. | Adjusted gMean ratio [%] | 77.55 | 2-Sided | 90 | 67.27 | 89.4 | Adjusted geometric Mean (gMean) ratio calculated as ratio of adjusted gMeans of (Treatment period 2: BI 425809 plus probe drugs) and (Treatment period 1: Probe drugs) multiplied by 100. | Other |